Journal
BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS
Volume 1867, Issue 4, Pages 405-415Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbapap.2019.01.007
Keywords
Insulin; hIAPP; Amyloid; NMR; AFM; beta-Breaker inhibitor
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Funding
- Council of Scientific and Industrial Research (CSIR), Govt. of India [02(0292)/17/EMR-II]
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Subcutaneous insulin delivery serves as the major treatment for the ever-increasing spread of type II diabetes worldwide. However, long-term exposure to insulin results in local aggregates at the site of injection. This therapeutic concern accentuates the need to develop newer effective excipients to stabilize the insulin in pharmaceutical formulations. The fact that in normal physiological conditions, insulin interacts with the amylin hormone co-secreted from the pancreas, we targeted a peptide-mimetic approach based on the amylin sequence. The amylin-fibrillating core (NL6-N(22)FGAIL(27) from the human Islet Amyloid Poly-Peptide) and its derivative NFGAXL (NL6X, X = 2-aminobenzoic acid) were used as potential inhibitory peptides against insulin amyloidogenesis. The fibrillation kinetics in the presence of the inhibitors was studied using an array of biophysical and microscopic techniques. High-resolution NMR spectroscopy enabled probing of the inhibitory interaction at an atomic resolution. Our results highlight the potential of using the naturally evolved NL6 peptide as an effective inhibitor against insulin fibrillation.
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